title: Mir-144 selectively regulates embryonic alpha-hemoglobin synthesis during primitive erythropoiesis.
abstract: Precise transcriptional control of developmental stage-specific expression and switching of alpha- and beta-globin genes is significantly important to understand the general principles controlling gene expression and the pathogenesis of thalassemia. Although transcription factors regulating beta-globin genes have been identified, little is known about the microRNAs and trans-acting mechanism controlling alpha-globin genes transcription. Here, we show that an erythroid lineage-specific microRNA gene, miR-144, expressed at specific developmental stages during zebrafish embryogenesis, negatively regulates the embryonic alpha-globin, but not embryonic beta-globin, gene expression, through physiologically targeting klfd, an erythroid-specific Krüppel-like transcription factor. Klfd selectively binds to the CACCC boxes in the promoters of both alpha-globin and miR-144 genes to activate their transcriptions, thus forming a negative feedback circuitry to fine-tune the expression of embryonic alpha-globin gene. The selective effect of the miR-144-Klfd pathway on globin gene regulation may thereby constitute a novel therapeutic target for improving the clinical outcome of patients with thalassemia.
authors.affiliation: Laboratory of Development and Diseases, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yan-Fang
authors.initials: YF
authors.lastname: Fu
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Du
authors.forename: Mei
authors.initials: M
authors.lastname: Dong
authors.forename: Kang-Yong
authors.initials: KY
authors.lastname: Zhu
authors.forename: Chang-Bin
authors.initials: CB
authors.lastname: Jing
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Fan
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.forename: Gui-Ping
authors.initials: GP
authors.lastname: Yue
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Qiu-Hua
authors.initials: QH
authors.lastname: Huang
authors.forename: Qing
authors.initials: Q
authors.lastname: Jing
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.forename: Ting Xi
authors.initials: TX
authors.lastname: Liu
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D019295:Computational Biology; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D055542:alpha-Globins / Q000235:genetics* / Q000378:metabolism; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; D009841:Oligonucleotides; D012333:RNA, Messenger; D029961:Zebrafish Proteins; D055542:alpha-Globins; D055544:beta-Globins; C485184:enhanced green fluorescent protein; C436493:klf1 protein, zebrafish; C477371:locked nucleic acid; D049452:Green Fluorescent Proteins